Tachykinins are a group of naturally occurring peptides found widely distributed throughout mammals, both within the central nervous system and in the peripheral nervous and circulatory systems. The three known mammalian tachykinins are Neurokinin-1 (NK-1, substance P), Neurokinin A, and Neurokinin B. These compounds act as neurotransmitters and immunomodulators and may contribute to the pathophysiology of a wide variety of human diseases.
Receptors for tachykinins have been identified and include neurokinin-1 (NK-1 or Substance P-preferring), NK-2 (Neurokinin A-preferring) and NK-3 (Neurokinin B-preferring). NK-1 receptor antagonists are being developed for the treatment of physiological conditions associated with an excess or imbalance of tachykinins, particularly substance P. Such conditions include affective disorders such as anxiety, depression, obsessive compulsive disorder, bulimia, and panic disorder. See Gentsch et al. Behav. Brain Res. 2002, 133, 363; Varty et al. Neuropsychopharmacology 2002, 27, 371; Papp et al. Behav. Brain Res. 2000, 115, 19; Kramer et al. Science 1998, 281, 1640; and Rosen et al. Bioorg. Med. Chem. Lett. 1998, 8, 281.
NK-1 antagonists are believed to modulate 5-HT function via noradrenergic pathways and have been shown to attenuate presynaptic 5-HT1A receptor function. Thus, the combination of serotonin reuptake inhibition with NK-1 antagonism may lead to new classes of drugs with improved characteristics.
Dual NK-1 antagonists-serotonin reuptake inhibitors have been reported. See Alvaro et al., PCT application WO 2004/005255; and Alvaro et al., PCT application WO 2004/005256; Ryckmans et al. Bioorganic and Medicinal Chemistry Letters 2002, 12, 261–264; MacLeod et al., U.S. Pat. No. 6,136,824.